Molecular structure of the human skin’s barrier : elucidation, formation and utilization

The main focus of this study is the permeation barrier of human skin. Original cryo-electron microscopic images from near native samples of human epidermis was used as the guiding reference to assemble in silico molecular models and also to assess the possibility of their presence in the barrier. Molecular dynamics and transmission electron microscopy simula- tions have been successively deployed to obtain models closer to a more naturally occurring state and attain simulated electron-microscopic images from them comparable to those from the real cryo-electron microscopy. The important questions that were investigated are: How is the barrier formation initiated? What are the transient structures involved and how do structural transformations advance during the formation process? What final structure does it form into?

The results show support for a hydrated and tightly folded cubic structure containing gly- cosylceramides as the starting structure, compatible with reference cryo-electron microscopy images from the topmost layer of the stratum granulosum. Furthermore it is shown how this structure has the ability to collapse into a lamellar structure after deglycosylation and dehydration. Subsequent stages of the development of the barrier are visible in the mi- croscopic data from the lowermost layers of stratum corneum. The data show uniform and non-uniform fine striped patterns. We attempted to arrive at molecular structures that could explain the cryo-electron microscopy patterns. Multiple systems were tested and the ones with the best match were selected as the most plausible model. The same procedure was applied to determine the structure of the fully formed barrier, which is thought to be the ma- jor obstacle for permeation of different substances into the body. It is further demonstrated how an accurate molecular model of the skin’s barrier structure can be utilized to predict some of its physical properties such as its permeability properties or thermotropic behaviour, revealing the capability of computer simulations in situations where the lab experiments are unwieldy or impossible.

List of scientific papers

I. A Narangifard, L den Hollander, Christian L Wennberg, M Lundborg, Erik Lindahl, I Iwai, H Han, S Masich, B Daneholt, and L Norlén. Human skin barrier formation takes place via a cubic to lamellar lipid phase transition as analyzed by cryoelectron microscopy and em-simulation. Experimental Cell Research. 366(2):139–151, 2018.
https://doi.org/10.1016/j.yexcr.2018.03.010

II. Christian L Wennberg, Ali Narangifard, Magnus Lundborg, Lars Norlén, and Erik Lindahl. Structural transitions in ceramide cubic phases during formation of the human skin barrier. Biophysical Journal. 114(5):1116–1127, 2018.
https://doi.org/10.1016/j.bpj.2017.12.039

III. Ali Narangifard, Christian L. Wennberg, Lianne den Hollander, Ichiro Iwai, HongMei Han, Lundborg Magnus, Sergej Masich, Lindahl Erik, Daneholt Bertil, and Lars Norlén. Molecular reorganization during formation of the human skin barrier studied in situ. [Manuscript]

IV. Magnus Lundborg, Christian L Wennberg, Ali Narangifard, Erik Lindahl, and Lars Norlén. Predicting drug permeability through skin using molecular dynamics simulation. Journal of Controlled Release. 283:269–279, 2018.
https://doi.org/10.1016/j.jconrel.2018.05.026